RNAs are essential for the functioning of a healthy nervous system, but the dysfunction of coding and noncoding RNAs causes many devastating neurodegenerative disorders. In Huntington's disease, CAG-repeat expansions encode polyglutamine tracts in one allele of the huntingtin gene. Both the CAG repeat-containing mRNAs and the translated polyQ protein cause pathology. The huntingtin transcript containing expanded CAG repeats adopts a structure distinct from that formed by the normal mRNA, and the unique disease-associated RNA tertiary structure is a prime target for the development of novel therapeutics. RNA is a compelling target for small-molecule drug discovery, and a three-dimensional RNA structure found only in the disease-associated huntingtin mRNA offers an opportunity for the development of allele-specific small molecules. Multiple natural products target ribosomal RNA, establishing proof of concept for RNA as a drug target; however, RNA-targeted drug discovery remains a nascent field. We are ideally positioned to develop, validate, and apply a screening system to identify small-molecule ligands that specifically target the unique tertiary structure adopted by the disease-related huntingtin mRNA. Our proposed screening platform combines an initial very rapid and high-throughput microarray screen with a secondary assay based on SHAPE technology, the gold standard for RNA structure analyses. This platform will include controls that enforce high specificity of ligand for the target RNA. Following successful validation of this platform in the R21 phase, we will apply the platform to identify small molecules that specifically bind to the disease-associated huntingtin allele in the R33 phase. Validation and initial medicinal chemistry development of hit compounds will serve as a foundation for the development of novel therapies for Huntington's disease with the opportunity to access an unprecedented level of selectivity. The majority of RNAs share broadly similar overall properties, so a strategy that allows RNA to be targeted in a single case will likely allow targeting of diverse therapeutically important RNAs. The long-term vision of Ribometrix is to apply this platform technology to discover small-molecule therapeutics that target functional RNA structures involved in indications for which there are no approved therapies, including Huntington's disease. We are poised to fully validate and apply an efficient and generic approach for RNA-targeted ligand discovery by targeting an RNA structure unique to the pathogenic disease-causing huntingtin allele.